Phase I/Ib Dose-escalation of Dinaciclib With Weekly Paclitaxel for Advanced Solid Tumor Malignancies & Assessment of MYC Oncogene Overexpression
This study is currently recruiting participants.
Verified August 2012 by University of California, San Francisco
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Jo Chien, University of California, San Francisco
First received: August 24, 2012
Last updated: August 30, 2012
Last verified: August 2012
The purpose of this trial is to collect safety data for the combination of weekly paclitaxel and dinaciclib in patients with advanced solid tumor malignancies. After the Phase 2 dose is determined, a 12 subject expansion cohort in patients with advanced triple negative breast cancer will be opened.
Malignant Solid Tumour
Triple-negative Breast Cancer
Drug: Dinaciclib & paclitaxel treatment
||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Phase I/Ib Dose-escalation Trial of the Cyclin-dependent Kinase Inhibitor Dinaciclib in Combination With Weekly Paclitaxel in Patients With Advanced Solid Tumor Malignancies and Assessment of MYC Oncogene Overexpression
Primary Outcome Measures:
- Maximum tolerated dose (MTD) [ Time Frame: Measured during Cycle 1 (28 Days) for each cohort, up to 3 cohorts (about 3 months) ] [ Designated as safety issue: Yes ]
The MTD is measured (safety/tolerability) by clinical review of relevant AE parameters (i.e. laboratory tests, physical exams)
- Define dose-limiting toxicities (DLTs) [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: Yes ]
Toxicities will be graded in severity per CTCAE version 4.0, based on events occurring during the first Cycle for each cohort
Secondary Outcome Measures:
- Anti-tumor activity in patients with advanced triple negative breast cancer [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: No ]
Response and progression will be evaluated using RECIST 1.1 criteria based on radiographic studies performed every 8 weeks
- Impact of paclitaxel on pharmacokinetics of dinaciclib [ Time Frame: Up to 8 Cycles (approx 8 months) ] [ Designated as safety issue: No ]
Plasma dinaciclib concentration-time data will be p taken (blood draws) pre-dose to post-dose (0-12 hr) to determine PK parameters (Cmax, Tmax, AUC)
- Biomarkers-dinaciclib activity [ Time Frame: Baseline to pre-Cycle 3 (approximately 3 months) ] [ Designated as safety issue: No ]
Biopsy tissue will be assesed at baseline/pre-treatment and pre-Cycle 3, to correlate the biomarkers relevant to dinaciclib activity and MYC expression with clinical response
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||December 2014 (Final data collection date for primary outcome measure)
Experimental: Dinaciclib & paclitaxel treatment
Weekly dinaciclib in combination with weekly paclitaxel
Drug: Dinaciclib & paclitaxel treatment
Weekly dinaciclib in combination with weekly paclitaxel
Other Name: Single Arm
This is a single-site, open-label phase I/Ib trial of weekly dinaciclib in combination with weekly paclitaxel in patients with advanced solid tumor malignancies. Any number of prior therapies is allowed. Prior treatment with paclitaxel is allowed. Paclitaxel will be administered weekly by 1-hour intravenous infusion at a fixed dose of 80 mg/m2 during a 28-day repeating cycle. Dinaciclib will be administered weekly by 2-hour intravenous infusion 24 hours later. Dinaciclib is the investigational agent and will be dose escalated using a 3+3 design. Only 2 cohorts are planned, although additional cohorts exploring intermediate doses or specific patient subsets may be added. The starting dinaciclib dose is 7 mg/m2. The primary objective is to define the maximum tolerated dose of dinaciclib when given weekly in this combination and schedule. The primary endpoint is safety and tolerability. Secondary objectives include evaluation of the preliminary efficacy of this combination and determination of pharmacokinetic interactions between dinaciclib and paclitaxel. Exploratory studies characterizing and correlating the biomarkers relevant to dinaciclib activity and MYC overexpression with clinical response will be performed.
|Ages Eligible for Study:
||18 Years to 85 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
Dose escalation cohorts
- Histologically or cytologically documented, incurable, unresectable locally advanced, or metastatic solid tumor malignancy
- The tumor biopsy is optional in the dose-finding phase of the protocol
- Patient is male or female and ≥ 18 years of age on the day of signing informed consent.
- Patient must have performance status of 0-2 on the ECOG Performance Scale and life expectancy > 3 months
- Patient must have evaluable disease
Patient must have adequate organ function as indicated by the following laboratory values:
- Absolute neutrophil count (ANC) ≥ 1,500 /μL
- Platelets ≥ 100,000 /μL
- Hemoglobin ≥ 9 g/dL
- Serum creatinine or calculated creatinine clearance ≤ 1.5 x upper limit of normal (ULN) OR
- ≥ 60 mL/min for patients with creatinine levels > 1.5 x institutional ULN
- Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
- Prothrombin time (PT)/INR ≤ 1.2 x ULN
- Partial thromboplastin time (PTT) ≤ 1.2 x ULN
- Potassium, Calcium, Phosphorus in normal range
- Uric Acid in normal range
- Female patient of childbearing potential must have a negative serum or urine pregnancy test β-hCG and agree to the use of effective methods of contraception while on study.
- Patient has voluntarily agreed to participate by giving written informed consent
- Prior taxane in the adjuvant or metastatic setting is allowed
- Any number of prior lines of chemotherapy in the metastatic setting is allowed
- Concomitant use of bisphosphonates is allowed
- Patients with stable and clinically insignificant CNS disease are allowed, patients must be off steroids with no new CNS symptoms or findings on radiographic imaging
Dose expansion cohort
- Histologically documented metastatic or locally advanced unresectable breast cancer that is ER and PR ≤ 10% expression and does not over-express HER2 protein (IHC 0, 1+, or 2+and FISH < 2.0)
- Patient must consent to a biopsy of a site of disease unless the only site of disease is lung/pleura
- Patient must have measureable disease
- All other inclusion criteria per the dose escalation cohorts
Both dose escalation and dose expansion cohorts
- Patient who has had radiotherapy or hormonal therapy within 2 weeks, chemotherapy within 3 weeks or 5 half-lives, whichever is shorter (6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from toxicity due to previous agents administered. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.
- Patients less than 4 weeks post major surgical procedure (all surgical wounds must be fully healed). For the purpose of this criterion, a major surgical procedure is defined as one requiring the administration of general anesthesia.
- Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of Study Day 1
- Patient has known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids. Patients with clinically insignificant brain metastases that do not require treatment are eligible.
- Patient has a primary central nervous system tumor
- Patient has known hypersensitivity to the components of study drug or its analogs. Patients who have had a hypersensitivity reaction to paclitaxel or products formulated with Cremophor® EL (polyoxyethylated castor oil) should not be enrolled in this study.
Patient has a history or current evidence of clinically significant heart disease including:
- Clinically significant congestive heart failure, unstable angina pectoris
- Clinically significant cardiac arrhythmia Myocardial infarction during the last 6 months, and/or a current ECG tracing that is abnormal in the opinion of the treating Investigator QTc prolongation > 450 msec (Bazett's Formula)
- Congenitally long QT syndrome, and/or current anti-arrhythmic therapy, has received any marketed or experimental compound in the last 4 weeks prior to entering the study with possible or known effects of QT prolongation, or cumulative high-dose anthracycline therapy.
- Patient with evidence of clinically significant bradycardia (HR < 50), or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV block (Mobitz Type 2), Patient with uncontrolled hypertension (≥ 140/90 mmHg). Patients who are controlled on antihypertensive medication will be allowed to enter the study.
- Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient‟s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Patient is, at the time of signing informed consent, a regular user of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.
- Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
- Patient is known to be Human Immunodeficiency Virus (HIV)-positive
- Patient has known history of active Hepatitis A, B, or C
- Patient has symptomatic ascites or pleural effusion, a patient who is clinically stable following treatment for these conditions is eligible
- Patient is receiving treatment with oral corticosteroids (physiologic replacement doses and inhaled corticosteroids are permitted)
- Patient has baseline neuropathy of ≥ grade 2
- Patients who have known allergic reactions to paclitaxel or IV contrast dye despite standard prophylaxis
- Patients who require medications that are strong CYP3A4 inhibitors or inducers. Patients who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose of dinaciclib.
- Patients requiring warfarin therapy, low molecular weight heparin is permitted
Please refer to this study by its ClinicalTrials.gov identifier: NCT01676753
|UCSF Helen Diller Family Comprehensive Cancer Center
|San Francisco, California, United States, 94143 |
|Contact: A. Jo Chien, MD 418-885-7577 Jo.Chien@ucsf.edu |
|Contact: Andrei Goga, MD, PhD 415-476-4191 firstname.lastname@example.org |
|Principal Investigator: A. Jo Chien, MD |
|Principal Investigator: Andrei Goga, MD, PhD |
|Sub-Investigator: Alain Algazi, MD |
|Sub-Investigator: Emily Bergsland, MD |
|Sub-Investigator: Mark Moasser, MD |
|Sub-Investigator: Robin Kate Kelley, MD |
|Sub-Investigator: Pamela Munster, MD |
|Sub-Investigator: Hope Rugo, MD |
Merck Sharp & Dohme Corp.
||A Jo Chien, MD
||University of California, San Francisco
No publications provided
||Jo Chien, UCSF Assistant Clinical Professor, University of California, San Francisco
History of Changes
|Other Study ID Numbers:
||UCSF CC# 12951
|Study First Received:
||August 24, 2012
||August 30, 2012
||United States: Food and Drug Administration
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on December 11, 2013
Neoplasms by Site
Cyclin-Dependent Kinase Inhibitor Proteins
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Protein Kinase Inhibitors